The adverse effects of the maternal consumption of alcohol on the fetus have been recognized for centuries. Fetal Alcohol Syndrome (FAS) is characterized by pre and postnatal growth retardation, mental retardation, behavioral deficits and facial deformities. In spite of numerous animal studies, the biochemical mechanism(s) by which alcohol produces its effects on the developing fetus are not well understood. Brain dysfunction has been associated with glutathione (GSH) deficiency. Several studies have shown that the administration of alcohol to adult rats produces a decrease in the hepatic levels of GSH. GSH has been shown to have a protective role in drug toxicity. Thiol compounds such as cysteine, a precursor of GSH, have ben shown to protect cells from damage produced by drugs which deplete GSH. Preliminary studies in our laboratory have shown liver and brain GSH levels are decreased in fetuses of rats that have received alcohol throughout pregnancy. GSH depletion was produced by alcohol doses that cause prenatal growth retardation. The administration of L-buthionine sulfoximine (BSO) to pregnant rats throughout gestation produced a decrease in GSH in the offspring and also produced prenatal growth retardation. Preliminary studies have also shown that alcohol-induced GSH depletion is prevented when N-acetyl-L-cysteine (NAC), a GSH precursor, is given concomitantly with alcohol. NAC treatment also abolished some of the alcohol-induced teratogenic effects. The experiments described in this proposal will test the following hypothesis: Teratogenesis produced by the in utero exposure to alcohol arises from reductions in fetal glutathione levels. We will explore further, the dose-response relationships between alcohol, glutathione depletion and teratogenicity. We will determine whether the teratogenic effects of alcohol are due, at least in part, to reduced levels of GSH in the fetus. We will determine if reducing maternal and fetal GSH levels with BSO will produce teratogenic effects in rats that mimic those produced by alcohol. We will also determine if BSO will potentiate alcohol-induced teratogenesis. We propose that the concomitant administration of alcohol and BSO will produce teratogenic effects in the offspring at lower alcohol doses than when alcohol is given by itself. It will be determined if NAC will have a protective action and decrease the teratogenic effects produced by alcohol. We hypothesize that the administration of NAC will prevent alcohol-induced GSH depletion and prevent alcohol-induced teratogenesis.